Project Summary A hallmark of osteoarthritis (OA) is the progressive loss of the joint articular cartilage (AC), the tissue that protects the moving surfaces of bones to facilitate the pain-free movement of the arms, legs, hands, and feet. At the cellular level, AC loss is caused by changes in the chondrocyte homeostasis, stable populations of cells present in the AC that produce the protective extracellular matrix proteins that facilitate AC durability. While it is known that damage to the AC can initiate changes in chondrocyte gene expression causal in OA, very little is known about the molecular mechanisms normally functioning to maintain stable chondrocyte phenotypes necessary for AC homeostasis. To address this knowledge gap, the proposed investigations will identify the complete cohort of loci regulated by lncRNA-HIT in the AC, as our research examining the epigenetic function of this lncRNA in AC indicates that it regulates several loci whose products contribute to chondrocyte stability. Exploiting this epigenetic function, lncRNA-HIT will also be evaluated as a protective therapeutic, using ectopic expression of the lncRNA in chondrocytes to ameliorate the onset and severity of AC loss in a murine model of OA. Finally, the epigenetic function of human LNCRNA-HIT will be examined for its capacity to mediate the in vitro differentiation of articular cartilage from human chondroprogenitors, providing a future avenue for therapeutic replacement of AC impacted by OA.